scholarly journals Cellular FLICE-inhibitory Protein Splice Variants Inhibit Different Steps of Caspase-8 Activation at the CD95 Death-inducing Signaling Complex

2001 ◽  
Vol 276 (23) ◽  
pp. 20633-20640 ◽  
Author(s):  
Andreas Krueger ◽  
Ingo Schmitz ◽  
Sven Baumann ◽  
Peter H. Krammer ◽  
Sabine Kirchhoff
Keyword(s):  
Splice Variants ◽  
Caspase 8 ◽  
Inhibitory Protein ◽  
Signaling Complex ◽  
Protein Splice

scholarly journals Hypo-Expression of Flice-Inhibitory Protein and Activation of the Caspase-8 Apoptotic Pathways in the Death-Inducing Signaling Complex Due to Ischemia Induced by the Compression of the Asphyxiogenic Tool on the Skin in Hanging Cases

Diagnostics ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 938
Author(s):  
Aniello Maiese ◽  
Alessandra De Matteis ◽  
Giorgio Bolino ◽  
Emanuela Turillazzi ◽  
Paola Frati ◽  
...  
Keyword(s):  
Tertiary Structure ◽  
Active Form ◽  
Three Dimensional ◽  
Death Receptor ◽  
Cell Receptor ◽  
Control Group ◽  
Caspase 8 ◽  
Inhibitory Protein ◽  
Signaling Complex ◽  
Induced Apoptosis

The FLICE-inhibitory protein (c-FLIPL) (55 kDa) is expressed in numerous tissues and most abundantly in the kidney, skeletal muscles and heart. The c-FLIPL has a region of homology with caspase-8 at the carboxy-terminal end which allows the molecule to assume a tertiary structure similar to that of caspases-8 and -10. Consequently, c-FLIPL acts as a negative inhibitor of caspase-8, preventing the processing and subsequent release of the pro-apoptotic molecule active form. The c-FLIP plays as an inhibitor of apoptosis induced by a variety of agents, such as tumor necrosis factor (TNF), T cell receptor (TCR), TNF-related apoptosis inducing ligand (TRAIL), Fas and death receptor (DR). Increased expression of c-FLIP has been found in many human malignancies and shown to be involved in resistance to CD95/Fas and TRAIL receptor-induced apoptosis. We wanted to verify an investigative protocol using FLIP to make a differential diagnosis between skin sulcus with vitality or non-vital skin sulcus in hanged subjects and those undergoing simulated hanging (suspension of the victim after murder). The study group consisted of 21 cases who died from suicidal hanging. The control group consisted of traumatic or natural deaths, while a third group consisted of simulated hanging cases. The reactions to the Anti-FLIP Antibody (Abcam clone-8421) was scored for each section with a semi-quantitative method by means of microscopic observation carried out with confocal microscopy and three-dimensional reconstruction. The results obtained allow us to state that the skin reaction to the FLIP is extremely clear and precise, allowing a diagnosis of unequivocal vitality and a very objective differentiation with the post-mortal skin sulcus.

scholarly journals Accelerated degradation of cFLIPL and sensitization of the TRAIL DISC-mediated apoptotic cascade by pinoresinol, a lignan isolated from Rubia philippinensis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
So-Ra Lee ◽  
Khong Trong Quan ◽  
Hee Sun Byun ◽  
InWha Park ◽  
Kidong Kang ◽  
...  
Keyword(s):  
De Novo ◽  
Biological Effects ◽  
Early Event ◽  
Caspase 8 ◽  
Glioblastoma Cells ◽  
Inhibitory Protein ◽  
Apoptotic Signaling ◽  
Signaling Complex ◽  
Highly Active ◽  
P53 Signaling

Abstract Plant-derived lignans have numerous biological effects including anti-tumor and anti-inflammatory activities. Screening of purified constituents of Rubia philippinensis from human glioblastoma cells resistant to TNF-related apoptosis-inducing ligand (TRAIL) has suggested that the lignan pinoresinol was a highly active TRAIL sensitizer. Here we show that treatment with nontoxic doses of pinoresinol in combination with TRAIL induced rapid apoptosis and caspase activation in many types of glioblastoma cells, but not in normal astrocytes. Analyses of apoptotic signaling events revealed that pinoresinol enhanced the formation of TRAIL-mediated death-inducing signaling complex (DISC) and complete processing of procaspase-8 within the DISC in glioblastoma cells, in which caspase-8 was inactivated. Mechanistically, pinoresinol downregulated the expression of cellular FLICE-inhibitory protein (cFLIPL) and survivin through proteasome-mediated degradation, without affecting death receptors or downstream intracellular apoptosis-related proteins. Furthermore, the sensitization of TRAIL-mediated apoptosis by pinoresinol strictly depended on the expression level of cFLIPL, which was regulated through de novo protein synthesis, rather than by NF-κB or p53 signaling. Taken together, our results indicate that pinoresinol facilitates DISC-mediated caspase-8 activation by targeting cFLIPL in an early event in apoptotic signaling, which provides a potential therapeutic module for TRAIL-based chemotherapy.

scholarly journals Cryo-EM structural analysis of FADD:Caspase-8 complexes defines the catalytic dimer architecture for co-ordinated control of cell fate

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Joanna L. Fox ◽  
Michelle A. Hughes ◽  
Xin Meng ◽  
Nikola A. Sarnowska ◽  
Ian R. Powley ◽  
...  
Keyword(s):  
Cell Death ◽  
Structural Analysis ◽  
Cell Fate ◽  
Catalytic Domain ◽  
Caspase 8 ◽  
Type I ◽  
Signaling Complex ◽  
Catalytic Domains ◽  
Regulated Cell Death ◽  
Death Effector

AbstractRegulated cell death is essential in development and cellular homeostasis. Multi-protein platforms, including the Death-Inducing Signaling Complex (DISC), co-ordinate cell fate via a core FADD:Caspase-8 complex and its regulatory partners, such as the cell death inhibitor c-FLIP. Here, using electron microscopy, we visualize full-length procaspase-8 in complex with FADD. Our structural analysis now reveals how the FADD-nucleated tandem death effector domain (tDED) helical filament is required to orientate the procaspase-8 catalytic domains, enabling their activation via anti-parallel dimerization. Strikingly, recruitment of c-FLIPS into this complex inhibits Caspase-8 activity by altering tDED triple helix architecture, resulting in steric hindrance of the canonical tDED Type I binding site. This prevents both Caspase-8 catalytic domain assembly and tDED helical filament elongation. Our findings reveal how the plasticity, composition and architecture of the core FADD:Caspase-8 complex critically defines life/death decisions not only via the DISC, but across multiple key signaling platforms including TNF complex II, the ripoptosome, and RIPK1/RIPK3 necrosome.

scholarly journals Alpha/Beta Interferons Potentiate Virus-Induced Apoptosis through Activation of the FADD/Caspase-8 Death Signaling Pathway

2000 ◽  
Vol 74 (3) ◽  
pp. 1513-1523 ◽  
Author(s):  
Siddharth Balachandran ◽  
P. Christopher Roberts ◽  
Todd Kipperman ◽  
Kapil N. Bhalla ◽  
Richard W. Compans ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Sindbis Virus ◽  
Influenza Virus Infection ◽  
Dominant Negative ◽  
Caspase 8 ◽  
Signaling Complex ◽  
Dependent Protein ◽  
Induced Apoptosis ◽  
Dominant Negative Variant

ABSTRACT Interferon (IFN) mediates its antiviral effects by inducing a number of responsive genes, including the double-stranded RNA (dsRNA)-dependent protein kinase, PKR. Here we report that inducible overexpression of functional PKR in murine fibroblasts sensitized cells to apoptosis induced by influenza virus, while in contrast, cells expressing a dominant-negative variant of PKR were completely resistant. We determined that the mechanism of influenza virus-induced apoptosis involved death signaling through FADD/caspase-8 activation, while other viruses such as vesicular stomatitis virus (VSV) and Sindbis virus (SNV) did not significantly provoke PKR-mediated apoptosis but did induce cytolysis of fibroblasts via activation of caspase-9. Significantly, treatment with IFN-α/β greatly sensitized the fibroblasts to FADD-dependent apoptosis in response to dsRNA treatment or influenza virus infection but completely protected the cells against VSV and SNV replication in the absence of any cellular destruction. The mechanism by which IFN increases the cells' susceptibility to lysis by dsRNA or certain virus infection is by priming cells to FADD-dependent apoptosis, possibly by regulating the activity of the death-induced signaling complex (DISC). Conversely, IFN is also able to prevent the replication of viruses such as VSV that avoid triggering FADD-mediated DISC activity, by noncytopathic mechanisms, thus preventing destruction of the cell.

Caspase-2 is activated at the CD95 death-inducing signaling complex in the course of CD95-induced apoptosis

Blood ◽  
2006 ◽  
Vol 108 (2) ◽  
pp. 559-565 ◽  
Author(s):  
Inna N. Lavrik ◽  
Alexander Golks ◽  
Simone Baumann ◽  
Peter H. Krammer
Keyword(s):  
B Cell ◽  
Molecular Mechanism ◽  
Cell Lines ◽  
Caspase 8 ◽  
Signaling Complex ◽  
Deficient Cell ◽  
Apoptotic Pathways ◽  
Caspase 2 ◽  
Induced Apoptosis

Caspase-2 was reported to be involved in a number of apoptotic pathways triggered by various stimuli. However, the molecular mechanism of procaspase-2 activation in the course of apoptosis remains poorly defined. In this report, we demonstrate that procaspase-2 is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex (DISC) in human T- and B-cell lines. We show that procaspase-2 is activated at the DISC on CD95 stimulation. Despite its presence at the DISC, caspase-2 does not initiate apoptosis on CD95 stimulation in caspase-8–deficient cell lines. Taken together, our data reveal that caspase-2 is activated at the DISC but does not play an initiating role in the CD95-induced apoptosis.

scholarly journals The Arabidopsis thaliana PeptideAtlas; harnessing world-wide proteomics data for a comprehensive community proteomics resource

2021 ◽  
Author(s):  
Klaas Jan van Wijk ◽  
Eric W Deutsch ◽  
Qi Sun ◽  
Zhi Sun ◽  
Tami Leppert ◽  
...  
Keyword(s):  
Splice Variants ◽  
Community Resources ◽  
Proteomics Data ◽  
Post Translational Modifications ◽  
Arabidopsis Proteome ◽  
Metadata Annotation ◽  
Protein Properties ◽  
Specific Proteins ◽  
Protein Splice ◽  
Splice Forms

We developed a new resource, the Arabidopsis PeptideAtlas (www.peptideatlas.org/builds/arabidopsis/), to solve central questions about the Arabidopsis proteome, such as the significance of protein splice forms, post-translational modifications (PTMs), or simply obtain reliable information about specific proteins. PeptideAtlas is based on published mass spectrometry (MS) analyses collected through ProteomeXchange and reanalyzed through a uniform processing and metadata annotation pipeline. All matched MS-derived peptide data are linked to spectral, technical and biological metadata. Nearly 40 million out of ~143 million MSMS spectra were matched to the reference genome Araport11, identifying ~0.5 million unique peptides and 17858 uniquely identified proteins (only isoform per gene) at the highest confidence level (FDR 0.0004; 2 non-nested peptides ≥ 9 aa each), assigned canonical proteins, and 3543 lower confidence proteins. Physicochemical protein properties were evaluated for targeted identification of unobserved proteins. Additional proteins and isoforms currently not in Araport11 were identified, generated from pseudogenes, alternative start, stops and/or splice variants and sORFs; these features should be considered for updates to the Arabidopsis genome. Phosphorylation can be inspected through a sophisticated PTM viewer. This new PeptideAtlas is integrated with community resources including TAIR, tracks in JBrowse, PPDB and UniProtKB. Subsequent PeptideAtlas builds will incorporate millions more MS data.

Immunoprecipitation of Death Inducing Signaling Complex by Caspase-8

2017 ◽  
pp. 19-31 ◽  
Author(s):  
Andrei Alexandru Constantinescu ◽  
Aymeric Morlé ◽  
Olivier Micheau
Keyword(s):  
Caspase 8 ◽  
Signaling Complex

Modulation of Caspase-8 and FLICE-Inhibitory Protein Expression as a Potential Mechanism of Epstein-Barr Virus Tumorigenesis in Burkitt’s Lymphoma

Blood ◽  
1999 ◽  
Vol 94 (5) ◽  
pp. 1727-1737 ◽  
Author(s):  
Clifford G. Tepper ◽  
Michael F. Seldin
Keyword(s):  
Cell Lines ◽  
Epstein Barr Virus ◽  
Burkitt’S Lymphoma ◽  
Burkitt's Lymphoma ◽  
Pcr Analysis ◽  
Caspase 8 ◽  
Rt Pcr ◽  
Inhibitory Protein ◽  
Barr Virus ◽  
Epstein Barr

Abstract Ligation of the Fas receptor induces death-inducing signaling complex (DISC) formation, caspase activation, and subsequent apoptotic death of several cell types. Epstein-Barr virus (EBV)-positive group III Burkitt’s lymphoma (BL) cell lines have a marked resistance to Fas-mediated apoptosis, although expressing each of the DISC components, Fas/ APO-1–associated death domain protein (FADD), and caspase-8 (FLICE/MACH/Mch5). The apoptotic pathway distal to the DISC is intact because ceramide analogs, staurosporine, and granzyme B activate caspase-3 and induce apoptosis. Fas resistance was not explained by the putative death-attenuating caspase-8 isoforms. However, while Fas-activated cytosolic extracts from sensitive cells were capable of processing both procaspase-8 and procaspase-3 into active subunit forms, resistant cell extracts did not possess either of these activities. Accordingly, reverse transcriptase-polymerase chain reaction (RT-PCR) analysis showed higher transcript levels for the FLICE-inhibitory protein (FLIPL) in resistant cells and the ratio of caspase-8 to FLIPLmeasured by competition RT-PCR analysis directly correlated with susceptibility to Fas-mediated apoptosis of all cell lines. In addition, modification of the caspase-8/FLIPL ratio by caspase-8 or FLIPL overexpression was able to alter the susceptibility status of the cell lines tested. Our results imply that the relative levels of caspase-8 and FLIPL are an important determinant of susceptibility to Fas-mediated apoptosis.

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